Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors

Andrea M Zuhl; Charles E Nolan; Michael A Brodney; Sherry Niessen; Kevin Atchison; Christopher Houle; David A Karanian; Claude Ambroise; Jeffrey W Brulet; Elizabeth M Beck; Shawn D Doran; Brian T O'Neill; Christopher W Am Ende; Cheng Chang; Kieran F Geoghegan; Graham M West; Joshua C Judkins; Xinjun Hou; David R Riddell; Douglas S Johnson

doi:10.1038/ncomms13042

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Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors

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Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors

Andrea M Zuhl, Charles E Nolan, Michael A Brodney, Sherry Niessen, Kevin Atchison, Christopher Houle, David A Karanian, Claude Ambroise, Jeffrey W Brulet, Elizabeth M Beck, …

Nature communications, Vol.7(1), pp.13042-13042

10/11/2016

DOI: 10.1038/ncomms13042

PMCID: PMC5062570

PMID: 27727204

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Abstract

Inhibition of β-secretase BACE1 is considered one of the most promising approaches for treating Alzheimer's disease. Several structurally distinct BACE1 inhibitors have been withdrawn from development after inducing ocular toxicity in animal models, but the target mediating this toxicity has not been identified. Here we use a clickable photoaffinity probe to identify cathepsin D (CatD) as a principal off-target of BACE1 inhibitors in human cells. We find that several BACE1 inhibitors blocked CatD activity in cells with much greater potency than that displayed in cell-free assays with purified protein. Through a series of exploratory toxicology studies, we show that quantifying CatD target engagement in cells with the probe is predictive of ocular toxicity in vivo. Taken together, our findings designate off-target inhibition of CatD as a principal driver of ocular toxicity for BACE1 inhibitors and more generally underscore the power of chemical proteomics for discerning mechanisms of drug action.

Details

Title: Subtitle: Chemoproteomic profiling reveals that cathepsin D off-target activity drives ocular toxicity of β-secretase inhibitors
Creators: Andrea M Zuhl - Worldwide Medicinal Chemistry
Charles E Nolan - Neuroscience Research Unit
Michael A Brodney - Worldwide Medicinal Chemistry
Sherry Niessen - Pfizer Worldwide Research and Development, San Diego, California 92121, USA
Kevin Atchison - Neuroscience Research Unit
Christopher Houle - Drug Safety Research and Development
David A Karanian - Drug Safety Research and Development
Claude Ambroise - Neuroscience Research Unit
Jeffrey W Brulet - Worldwide Medicinal Chemistry
Elizabeth M Beck - Worldwide Medicinal Chemistry
Shawn D Doran - Pharmacokinetics, Dynamics and Metabolism
Brian T O'Neill - Pfizer Worldwide Research and Development, Groton, Connecticut 06340, USA
Christopher W Am Ende - Pfizer Worldwide Research and Development, Groton, Connecticut 06340, USA
Cheng Chang - Pharmacokinetics, Dynamics and Metabolism
Kieran F Geoghegan - Structural Biology and Biophysics Group
Graham M West - Structural Biology and Biophysics Group
Joshua C Judkins - Worldwide Medicinal Chemistry
Xinjun Hou - Worldwide Medicinal Chemistry
David R Riddell - Neuroscience Research Unit
Douglas S Johnson - Worldwide Medicinal Chemistry
Resource Type: Journal article
Publication Details: Nature communications, Vol.7(1), pp.13042-13042
DOI: 10.1038/ncomms13042
PMID: 27727204
PMCID: PMC5062570
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Language: English
Date published: 10/11/2016
Academic Unit: Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984094575802771

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